Orally administrable opioid formulations having extended duration of effect

• US 6,294,195 B1
• Filed: 09/07/1999
• Issued: 09/25/2001
• Est. Priority Date: 12/24/1991
• Status: Expired due to Fees

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P.
• Inventors: Oshlack, Benjamin, Chasin, Mark
• Primary Examiner(s): Spear, James M.
• Application Number:
  US09/390,719
• Time in Patent Office: 749 Days
• Field of Search: 424/490, 424/468, 424/457, 424/458, 424/459, 424/494, 424/498, 424/496, 424/497, 424/460, 424/461, 424/462, 424/484, 424/486, 424/487, 424/488, 424/451, 424/456, 424/489
• US Class Current: 424/457
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2072 characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms A61K9/0004, A61K9/0056, A61K9/0065 take precedence
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Sustained release oral solid dosage forms of opioid analgesics are provided as multiparticulate systems which are bioavailable and which provide effective blood levels of the opioid analgesic for at least about 24 hours. A unit dose of the opioid analgesic contains a plurality of substrates including the opioid analgesic in sustained release form. The substrates have a diameter from about 0.1 mm to about 3 mm.

Claims

1. A bioavailable sustained-release oral analgesic dosage form for once-a-day administration, comprising:

a unit dose comprising an analgesically effective amount of a plurality of pharmaceutically acceptable matrices comprising an opioid analgesic or a salt thereof, and a hydrophobic material selected from the group consisting of an alkylcellulose, an acrylic resin and mixtures thereof, said matrices further comprising at least one C₁₂ to C₃₆ aliphatic alcohol, each of said matrices having a diameter from about 0.1 mm to about 3 mm, said dosage form being bioavailable and providing a therapeutic effect for about 24 hours or more after oral administration to a human patient.

3. The dosage form of claim 1, wherein said matrices further comprise at least one polyalkylene glycol.

4. The dosage form of claim 1, wherein said C₁₂ to C₃₆ aliphatic alcohol is stearyl alcohol.

5. The dosage form of claim 1, wherein said opioid analgesic is selected form the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone, dihydrocodeine, dihydromorphine, tramadol, and mixtures thereof.

6. The dosage form of claim 1, wherein said opioid analgesic is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacyl morphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, salts thereof and mixtures thereof.

7. The dosage form of claim 5, wherein said opioid analgesic consists of from about 2 mg to about 64 mg hydromorphone.

8. The dosage form of claim 5, wherein said opioid analgesic consists of from about 5 mg to about 800 mg morphine.

9. The dosage form of claim 1, wherein said opioid analgesic consists of from about 5 mg to about 400 mg oxycodone.

10. The dosage form of claim 1 which provides a peak plasma level of said opioid in-vivo from about 2 to about 10 hours after administration.

11. The dosage form of claim 1 which provides a peak plasma level of said opioid in-vivo from about 2 to about 4 hours after administration.

12. The dosage form of claim 1, wherein said matrices further comprise a hydroxyalklcellulose selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose and mixtures of any of the foregoing.

13. The dosage form of claim 12, wherein said hydroxyalkylcellulose is hydroxyethylcellulose.

14. The dosage form of claim 1, wherein said unit dose of said matrices are contained within a hard gelatin capsule.

15. The dosage form of claim 1, wherein said matrices have a diameter from about 0.5 mm to about 2 mm.

17. The dosage form of claim 1, further comprising release-modifying agents, said release-modifying agents comprising one or more hydrophilic polymers.

18. A dosage form of claim 1, further comprising a non-opioid drug.

19. The dosage form of claim 18, wherein the said non-opioid drug is a non-steroidal anti-inflammatory agent.

20. The dosage form of claim 19, wherein said non-steroidal anti-inflammatory agent is selected from the group consisting of ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam, and mixtures of any of the foregoing.

21. The dosage form of claim 1, wherein said opioid analgesic consists of tramadol or a salt thereof.

22. The dosage form of claim 1, wherein said alkylcellulose is ethylcellulose.

2. A bioavailable sustained-release oral analgesic dosage form for once-a-day administration, comprising:

a unit dose comprising a plurality of pharmaceutically acceptable matrices comprising an analgesically effective amount of hydromorphone or a salt thereof, ethylcellulose and stearyl alcohol, each of said matrices having a diameter from about 0.1 mm to about 3 mm, said dosage form being bioavailable and providing a therapeutic effect for about 24 hours or more after oral administration to a human patient.

23. The dosage form of claim 2 which provides a peak plasma level of said opioid in-vivo from about 2 to about 10 hours after administration to a patient or a population of patients.

24. The dosage form of claim 2 which provides a peak plasma level of said opioid in-vivo from about 2 to about 4 hours after administration to a patient or a population of patients.

16. A bioavailable sustained-release oral analgesic dosage form for once-a-day administration, comprising:

a unit dose comprising a plurality of pharmaceutically acceptable matrices comprising an analgesically effective amount of tramadol or a salt thereof, ethylcellulose and stearyl alcohol, each of said matrices having a diameter from about 0.1 mm to about 3 mm, said dosage form being bioavailable and providing a therapeutic effect for about 24 hours or more after oral administration to a human patient.

25. The dosage form of claim 16 which provides a peak plasma level of said opioid in-vivo from about 2 to about 10 hours after administration to a patient or a population of patients.

26. The dosage form of claim 16 which provides a peak plasma level of said opioid in-vivo from about 2 to about 4 hours after administration to a patient or a population of patients.